DESCRIPTION (provided by investigator): The fundamental hypothesis of our research is that molecular events initiated by agents acting at serotonin receptors in Drosophila, and other animal models, represent potential candidates for involvement in the development and etiology of neuropsychiatric disorders in humans, and importantly, may be targets for new avenues of discovery for therapeutics. The goal of this project is to develop the fruit fly, Drosophila melanogaster, as a genetically tractable model system to investigate molecular mechanisms underlying human neuropsychiatric disorders that involve serotonin. We propose to treat flies with specific serotonergic agents, including psychotomimetics and antipsychotics, to assess behavioral outcomes, and to develop the genetic tools necessary to elucidate the pathways linking receptor activation with behavior. As shown with most previously studied processes in Drosophila, ranging from development to drug response, the molecular and cellular events underlying serotonergic function are likely to be highly conserved between the fly and humans. The use of the fly to study these conserved neurochemical events brings into play extremely powerful genetic techniques to rapidly elucidate key pathways and molecules that otherwise could take years, at a substantially greater cost, to identify by traditional mammalian-based methods. Importantly, the fly is believed to express a functional ortholog of the mammalian 5-HT2 receptor, as well as orthologs of the mammalian 5-HT1A, 5-HT7, dopamine D1 and D2, GABA, NMDA, and metabotropic glutamate receptors, all of which have been strongly implicated in a variety of human neuropsychiatric disorders. Here, we propose investigations to develop this fly model by characterizing the: 1) neuropharmacology, 2) circuitry, and 3) behaviors of the Drosophila CNS serotonin system using molecular, genetic, pharmacological, and behavioral experiments to lay the foundation and create a knowledge base of serotonergic function in Drosophila, with a view toward developing the fly as a model genetic system to use in concert with ongoing proposed mammalian target identification experiments. Together, these experiments form a novel systems-based approach to explore neurochemical events relevant to neuropsychiatric disorders in humans, and will be of great importance to facilitate the discovery of novel targets for therapeutics. Schizophrenia is a debilitating neuropsychiatric disorder that affects about one out of every 100 Americans at a cost to the U.S. economy of nearly $63 billion/year. New approaches towards understanding underlying schizophrenia mechanisms are urgently needed in order to further understand and treat this disease, as well as other psychiatric disorders. We propose to develop the fruit fly, Drosophila melanogaster, as a model system to study the underlying serotonin neurochemistry of these diseases. The development and utilization of this model system will lead to an enhanced discovery rate of novel targets for therapeutics to treat these conditions. [unreadable] [unreadable]